Multiple sclerosis (MS) is a demyelinating disease characterized by chronic inflammation of the central nervous system in which many factors (genetic and environmental) may act together to influence disease susceptibility and progression (Frohman et al., 2006; Keegan and Noseworthy, 2002). While a large body of work has enhanced an understanding of the fundamental nature of MS, basic research into its etiology, pathophysiology, and treatment faces enormous challenges, and this may in part be due to the great variability in the clinical presentation and course of MS (Compston and Coles, 2008; Frohman et al., 2006; Keegan and Noseworthy, 2002).
Relapsing-remitting multiple sclerosis (RRMS) is one of the two main forms of the disease, the other being primary-progressive multiple sclerosis (PPMS). RRMS is characterized by periods of worsening neurologic function (Lublin et al., 2014; Polman et al., 2011). These periods, termed relapses or flare-ups, are followed by partial or complete recovery periods (remissions), during which symptoms improve partially or completely, and there is no apparent disease progression. RRMS is the most common disease course at the time of diagnosis (Lublin et al., 2014; Polman et al., 2011). Approximately 85 percent of people are initially diagnosed with RRMS, compared to 10-15 percent with progressive forms of the disease (Lublin et al., 2014; Polman et al., 2011). RRMS is defined by inflammatory attacks on myelin, as well as the nerve fibers themselves (Lublin et al., 2014; Polman et al., 2011). During these inflammatory attacks, activated immune cells cause small, localized areas of damage which produce the symptoms of MS (Lublin et al., 2014; Polman et al., 2011). Because the location of the damage is so variable, no two people have exactly the same symptoms.
While RRMS is defined by attacks of inflammation (relapses) in the central nervous system (CNS), the progressive form of MS involves much less of this type of inflammation. Subjects with RRMS tend to have more brain lesions, also called plaques or scars, detectable via magnetic resonance imaging (MRI) scans, and these lesions contain more inflammatory cells. Subjects with PPMS tend to have more spinal cord lesions, which contain fewer inflammatory cells.
A subject is diagnosed as having RRMS when test results provide evidence of at least two separate areas of damage to the myelin in the CNS that have occurred at different points in time (nationalmssociety.org). Tests that may be used to determine whether there is relevant damage to myelin in a subject include magnetic resonance imaging (MRI), visual evoked potential (VEP) testing, and analysis of the cerebrospinal fluid (nationalmssociety.org).
These tests have drawbacks, including pain, risks and costs. For example, a brain MRI is an expensive test that is hard to tolerate by claustrophobic patients. In addition, identification of active lesions on a brain Mill requires the administration of the gadolinium to a subject, which poses significant risks of allergic reactions and gadolinium-associated nephrogenic systemic fibrosis (Grobner T., 2006; Hellman, R., 2011). Indeed, gadolinium associated nephrogenic systemic fibrosis is a systemic, sometimes fatal (mortality rate up to 30%), disabling disease, mimicking scleroderma (Grobner T., 2006; Hellman, R., 2011).
The development of additional means for diagnosing a subject as having RRMS or determining whether a subject already diagnosed with MS is experiencing a relapse will greatly aid clinicians in quickly and accurately prescribing appropriate treatment. The present invention is directed to these and other important goals.